Apoptosis is a process of gene directed or programmed cell death which plays a significant role in a variety of biological processes. For example the regulation of this pathway has implications for both the pathogenesis and treatment of cancer. Little is yet known about the genes which regulate apoptotic cell death. This proposal focuses on normal and neoplastic B-cell development in the bursa of Fabrcius as a model experimental system for isolating and characterizing such genes. We have recently shown that both low dose irradiation and mechanical disruption of cell contacts in bursal follicles rapidly triggers apoptosis in the total lymphoid of normal embryonic bursal follicles. Myc oncogene induced preneoplastic bursal stem cells are hypersensitive to induction of cell death while apoptosis is actively suppressed in neoplasms derived from such cells. This proposal contains three specific aims. First, we plan to over express a negative regulator of apoptosis, Bcl-2, in bursal cells using a retroviral vector. We will determine if Bcl-2 can protect normal embryonic and/or preneoplastic bursal stem cells from apoptosis and the phenotypic consequences of such protection on normal and neoplastic B-cell development in the bursa using bursal transplantation techniques. Second, we will insert in viral vectors cDNA libraries we have prepared from bursal cell types in which apoptosis appears to be actively suppressed. By isolating viruses from such libraries which protect bursal cells from apoptosis we hope to clone and characterize genes which negatively regulate the cell death pathway. Third, if this approach appears to be successful, we plan selective screening of cDNA libraries from other cell types and other species to determine if this system might be useful for isolating functionally conserved cell death regulatory genes.